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Hajj is associated with an increased risk of the transmission of infectious diseases including upper respiratory tract infections (URTIs). It can be a focal point for the emergence, persistence and dissemination of antimicrobial-resistant (AMR) bacteria. The overuse of antibiotics during Hajj can promote the development of antimicrobial resistance. Little information is known regarding the true appropriateness of prescribing antibiotics for treating URTIs during Hajj. Here we studied the rate, patterns and appropriateness of antibiotic prescription among a cohort of pilgrims who were treated for URTIs during the 2018 Hajj season. Adult pilgrims who sought medical services for URTIs [presenting with coryza, runny nose, nasal irritation, nasal congestion, cough, sore throat, headache or fever (even if subjective)] within the Holy sites were enrolled in this study and consented to provide swabs and medical information. A total of 121 pilgrims were enrolled, with the majority (60.3 %) originating from North African Arab countries. Most were male (89.3 %) with a median age of 45 years. Bacterial infections were detected in 7.3 % (n=9) of the URTI cases. The identified bacteria included Haemophilus influenzae (n=6, all resistant to ampicillin), Streptococcus pneumoniae (n=2), Staphylococcus aureus (n=1, resistant to oxacillin) and Moraxella catarrhalis (n=1, resistant to ampicillin and trimethoprim/sulfamethoxazole). The antibiotic prescription rate was 52.1%, most of which was amoxicillin (81 %). The data demonstrated that the proportion of appropriate practices in treating bacterial URTIs in this cohort was 45.5 %. This study highlights the need for implementing laboratory identification of the aetiological agents and related AMR profiles when treating URTIs in Hajj, rather than relying on clinical assessment alone.

Enterotoxigenic Escherichia coli (ETEC) expressing the colonization pili CFA/I are common causes of diarrhoeal infections in humans. Here, we use a combination of transposon mutagenesis and transcriptomic analysis to identify genes and pathways that contribute to ETEC persistence in water environments and colonization of a mammalian host. ETEC persisting in water exhibit a distinct RNA expression profile from those growing in richer media. Multiple pathways were identified that contribute to water survival, including lipopolysaccharide biosynthesis and stress response regulons. The analysis also indicated that ETEC growing in vivo in mice encounter a bottleneck driving down the diversity of colonizing ETEC populations.

Enterotoxigenic

COVID-19 poses grave challenges for mass gatherings. One of the world’s largest annual gatherings, Arbaeen, occurs in Iraq. We studied respiratory symptoms and risk and protective factors using representative sampling of Arbaeen pilgrims in 2019 to inform prevention of COVID-19 transmission. Structured sampling was used to recruit walking pilgrims. A questionnaire asked about respiratory symptoms, risk, and preventive factors, including hygiene-related resources of toilet facilities. The commonest symptom reported by the 1842 participants (63.3% male, 36.7% female) was cough (25.6%). Eating in mawkibs (rest areas) with indoor kitchens and drinking only packaged water were associated with lower risk of cough (AOR = 0.72, CI = 0.56–0.94, AOR = 0.60, CI = 0.45–0.78, p &lt, 0.05). Facemask use was associated with increased risk of cough (AOR = 2.71, CI = 2.08–3.53, p &lt, 0.05). Handwashing was not protective against cough, or against (one or more of) cough, fever, or breathlessness in multivariate analysis. Toilet facilities often lacked running water (32.1%) and soap (26.1%), and had shared hand towels (17%). To reduce risk of respiratory infections including COVID-19 during Arbaeen or other mass gatherings, needs include running water, soap, and hygienic hand drying options or hand sanitiser. Education on proper handwashing and facemask approaches and monitoring around food preparation and eating spaces are needed.

Foodborne-associated bacteria with increased incidence of antimicrobial drug resistance were the most common cause., Hajj, the annual Muslim pilgrimage to Mecca, Saudi Arabia, is a unique mass gathering event that raises public health concerns in the host country and globally. Although gastroenteritis and diarrhea are common among Hajj pilgrims, the microbial etiologies of these infections are unknown. We collected 544 fecal samples from pilgrims with medically attended diarrheal illness from 40 countries during the 2011–2013 Hajj seasons and screened the samples for 16 pathogens commonly associated with diarrheal infections. Bacteria were the main agents detected, in 82.9% of the 228 positive samples, followed by viral (6.1%) and parasitic (5.3%) agents. Salmonella spp., Shigella/enteroinvasive Escherichia coli, and enterotoxigenic E. coli were the main pathogens associated with severe symptoms. We identified genes associated with resistance to third-generation cephalosporins ≈40% of Salmonella- and E. coli–positive samples. Hajj-associated foodborne infections pose a major public health risk through the emergence and transmission of antimicrobial drug–resistant bacteria.

Background Atypical Beijing genotype Mycobacterium tuberculosis strains are widespread in South Africa and have acquired resistance to up to 13 drugs on multiple occasions. It is puzzling that these strains have retained fitness and transmissibility despite the potential fitness cost associated with drug resistance mutations. Methods We conducted Illumina sequencing of 211 Beijing genotype M. tuberculosis isolates to facilitate the detection of genomic features that may promote acquisition of drug resistance and restore fitness in highly resistant atypical Beijing forms. Phylogenetic and comparative genomic analysis was done to determine changes that are unique to the resistant strains that also transmit well. Minimum inhibitory concentration (MIC) determination for streptomycin and bedaquiline was done for a limited number of isolates to demonstrate a difference in MIC between isolates with and without certain variants. Results Phylogenetic analysis confirmed that two clades of atypical Beijing strains have independently developed resistance to virtually all the potent drugs included in standard (pre-bedaquiline) drug-resistant TB treatment regimens. We show that undetected drug resistance in a progenitor strain was likely instrumental in this resistance acquisition. In this cohort, ethionamide (ethA A381P) resistance would be missed in first-line drug-susceptible isolates, and streptomycin (gidB L79S) resistance may be missed due to an MIC close to the critical concentration. Subsequent inadequate treatment historically led to amplification of resistance and facilitated spread of the strains. Bedaquiline resistance was found in a small number of isolates, despite lack of exposure to the drug. The highly resistant clades also carry inhA promoter mutations, which arose after ethA and katG mutations. In these isolates, inhA promoter mutations do not alter drug resistance, suggesting a possible alternative role. Conclusion The presence of the ethA mutation in otherwise susceptible isolates from ethionamide-naïve patients demonstrates that known exposure is not an adequate indicator of drug susceptibility. Similarly, it is demonstrated that bedaquiline resistance can occur without exposure to the drug. Inappropriate treatment regimens, due to missed resistance, leads to amplification of resistance, and transmission. We put these results into the context of current WHO treatment regimens, underscoring the risks of treatment without knowledge of the full drug resistance profile.

Antimicrobial resistance (AMR) is the major issue posing a serious global health threat. Low- and middle-income countries are likely to be the most affected, both in terms of impact on public health and economic burden. Recent studies highlighted the role of resistance networks on the transmission of AMR organisms, with this network being driven by complex interactions between clinical (e.g., human health, animal husbandry and veterinary medicine) and other components, including environmental factors (e.g., persistence of AMR in wastewater). Many studies have highlighted the role of wastewater as a significant environmental reservoir of AMR as it represents an ideal environment for AMR bacteria (ARB) and antimicrobial resistant genes (ARGs) to persist. Although the treatment process can help in removing or reducing the ARB load, it has limited impact on ARGs. ARGs are not degradable; therefore, they can be spread among microbial communities in the environment through horizontal gene transfer, which is the main resistance mechanism in most Gram-negative bacteria. Here we analysed the recent literature to highlight the contribution of wastewater to the emergence, persistence and transmission of AMR under different settings, particularly those associated with mass gathering events (e.g., Hajj and Kumbh Mela).

Antimicrobial resistance (AMR) is a major issue that poses a serious threat to global health. Recent reports from the World Health Organization (WHO) highlighted the increased threat from continuously emerging AMR organisms, accompanied by the paucity of development of new antimicrobial drugs. Low- and middle-income countries are likely to be the most affected, both in terms of the impact on public health and economic burden.

Antimicrobial resistance (AMR) is a global public health issue. Upper respiratory tract infections (URTIs) are common illnesses during Hajj, for which antibiotics are often inappropriately prescribed. Hajj healthcare workers’ (HCW) knowledge, attitudes and perceptions (KAP) about AMR and antibiotic use for URTIs are not known. We conducted a survey among HCWs during Hajj to explore their KAP regarding antibiotic use for URTIs in pilgrims. Electronic or paper-based surveys were distributed to HCWs during the Hajj in 2016 and 2017. A total of 85 respondents aged 25 to 63 (median 40) years completed the surveys. Most participants were male (78.8%) and were physicians by profession (95.3%). Around 85% and 19% of respondents claimed to have heard about AMR and antimicrobial stewardship programs, respectively, among whom most had obtained their knowledge during their qualification. Implementation of URTI treatment guidelines was very low. In conclusion, HCWs at Hajj have significant knowledge gaps regarding AMR, often do not use standard clinical criteria to diagnose URTIs and display a tendency to prescribe antibiotics for URTIs.

Summary Background In many countries, regular monitoring of the emergence of resistance to anti-tuberculosis drugs is hampered by the limitations of phenotypic testing for drug susceptibility. We therefore evaluated the use of genetic sequencing for surveillance of drug resistance in tuberculosis. Methods Population-level surveys were done in hospitals and clinics in seven countries (Azerbaijan, Bangladesh, Belarus, Pakistan, Philippines, South Africa, and Ukraine) to evaluate the use of genetic sequencing to estimate the resistance of Mycobacterium tuberculosis isolates to rifampicin, isoniazid, ofloxacin, moxifloxacin, pyrazinamide, kanamycin, amikacin, and capreomycin. For each drug, we assessed the accuracy of genetic sequencing by a comparison of the adjusted prevalence of resistance, measured by genetic sequencing, with the true prevalence of resistance, determined by phenotypic testing. Findings Isolates were taken from 7094 patients with tuberculosis who were enrolled in the study between November, 2009, and May, 2014. In all tuberculosis cases, the overall pooled sensitivity values for predicting resistance by genetic sequencing were 91% (95% CI 87–94) for rpoB (rifampicin resistance), 86% (74–93) for katG, inhA, and fabG promoter combined (isoniazid resistance), 54% (39–68) for pncA (pyrazinamide resistance), 85% (77–91) for gyrA and gyrB combined (ofloxacin resistance), and 88% (81–92) for gyrA and gyrB combined (moxifloxacin resistance). For nearly all drugs and in most settings, there was a large overlap in the estimated prevalence of drug resistance by genetic sequencing and the estimated prevalence by phenotypic testing. Interpretation Genetic sequencing can be a valuable tool for surveillance of drug resistance, providing new opportunities to monitor drug resistance in tuberculosis in resource-poor countries. Before its widespread adoption for surveillance purposes, there is a need to standardise DNA extraction methods, recording and reporting nomenclature, and data interpretation. Funding Bill & Melinda Gates Foundation, United States Agency for International Development, Global Alliance for Tuberculosis Drug Development.

Background Respiratory syncytial virus (RSV) is the leading cause of viral pneumonia and bronchiolitis, especially in younger children. The burden of RSV infection in adults, particularly in the older age group, is increasingly recognised. However, RSV disease burden and molecular epidemiology in the World Health Organization (WHO) Western Pacific Region (WPR) has not been reviewed systematically. The aim of this systematic review is to investigate the epidemiological aspects of RSV (incidence, prevalence, seasonality and hospitalisation status) and the associated molecular data in the WPRO countries. Methods A systematic search was conducted in international literature databases (MEDLINE, EMBASE, Scopus and Web of Science) to identify RSV-related publications from January 2000 to October 2017 in the WPR countries. Results A total of 196 studies from 15 WPR countries were included. The positivity rate for RSV among respiratory tract infection patients was 16.73% (95% confidence interval (CI) = 15.12%-18.4%). The RSV-positive cases were mostly found in hospitalised compared with outpatients (18.28% vs 11.54%, P

More human deaths have been attributable to Mycobacterium tuberculosis than any other pathogen, and the epidemic is sustained by ongoing transmission. Various typing schemes have been developed to identify strain-specific differences and track transmission dynamics in affected communities, with recent introduction of whole genome sequencing providing the most accurate assessment. Mycobacterial interspersed repetitive unit (MIRU) typing is a family of variable number tandem repeat schemes that have been widely used to study the molecular epidemiology of M. tuberculosis. MIRU typing was used in most well-resourced settings to perform routine molecular epidemiology. Instances of MIRU homoplasy have been observed in comparison with sequence-based phylogenies, limiting its discriminatory value. A fundamental question is whether the observed homoplasy arises purely through stochastic processes, or whether there is evidence of natural selection. We compared repeat numbers at 24 MIRU loci with a whole genome sequence-based phylogeny of 245 isolates representing three modern M. tuberculosis lineages. This analysis demonstrated extensive homoplasy of repeat numbers, but did not detect any evidence of natural selection of repeat numbers, at least since the ancestral branching of the three modern lineages of M. tuberculosis. In addition, we observed good sensitivity but poor specificity and positive predictive values of MIRU-24 to detect clusters of recent transmission, as defined by whole-genome single nucleotide polymorphism analysis. These findings provide mechanistic insight, and support a transition away from VNTR-based typing toward sequence-based typing schemes for both research and public health purposes.

Salmonella enterica serovar Wangata is an important pathogen in New South Wales (NSW), Australia. The incidence of S. Wangata is increasing and transmission is suspected to be via a non-food source. A recent outbreak investigation of sources of S. Wangata recovered isolates from humans, domestic animals, wildlife and the environment. Here, we extend that investigation by characterising and describing the genomic determinates of these isolates. We found that Australian S. Wangata isolates from different sources exhibited similar virulence and antimicrobial resistance gene profiles. There were no major genomic differences between isolates obtained from different geographical regions within Australia or from different host species. In addition, we found evidence (low number of SNPs and identical virulence gene profiles) suggestive of an international transmission event between Australia and the United Kingdom. This study supports the hypothesis that S. Wangata is shared between different hosts in NSW, Australia and provides strong justification for the continued use of genomic surveillance of Salmonella.

Summary Background Mongolia has high and rising rates of multi-drug resistant tuberculosis (MDR-TB). Spatio-temporal and programmatic evidence suggests a major contribution from MDR-TB transmission, but genotypic evidence has not been assessed. Methods All MDR-TB cases identified during 2012 were examined. Demographic and bacteriological data were obtained from the National Tuberculosis Reference Laboratory. Isolates of Mycobacterium tuberculosis from culture-confirmed category 1 treatment failures were genotyped using 24-loci mycobacterium interspersed repetitive unit (MIRU-24) analysis. Results Of the 210 MDR-TB cases identified, 115 (54.8%) were treatment failures (34.8% category 1; 20.0% category 2). Streptomycin resistance was present in 156 (74.3%) cases; including 55/73 (75.3%) category 1 treatment failures who had never been exposed to streptomycin. Among category 1 treatment failures, Beijing lineage strains predominated (88.0%; 59/67 of genotyped isolates). MIRU-24 clustering was documented in 62.7% (42/67) of strains; 55.2% (37/67) remained clustered when drug susceptibility test results were considered. In total 59.5% (25/42) of clustered strains were Beijing lineage and demonstrated in-vitro resistance to all first-line drugs tested. Conclusion The MDR-TB epidemic in Mongolia appears to be driven by primary transmission of Beijing lineage strains resistant to all first-line drugs. Enhanced infection control strategies together with early MDR-TB case detection and appropriate treatment are necessary to limit escalation of the MDR-TB epidemic.

Background Bougainville, an autonomous region of Papua New Guinea (PNG) is slowly improving services and infrastructure destroyed 20 years ago during the ten year civil war. However, the region still faces significant constraints to economic growth and human development and remains under-developed compared to PNG and close Pacific neighbours. PNG's 2017 Human Development Category (HDC) was one of the lowest at 0.544. The Bougainville Strategic Development Plan 2018–2022 noted significant gaps in health services and infrastructure, had inadequate water and waste disposal and experienced weak markets and cocoa quality. This research examines domestic conditions and the extent to which they impact on livelihoods. Method A cross-sectional livelihood survey was administered to cocoa growing households in 33 Village Assemblies (VAs) with 11 VAs in each of the three regions. Results Data was collected from 5172 individuals. A significant majority of households reported multiple health issues, rudimentary housing, unimproved sanitation and unimproved water. Over two-thirds of cocoa growers did not sell any cocoa bags in 2014–2016 resulting in low incomes and greater food insecurity compared to families selling cocoa. Families that produced no saleable cocoa were more likely to have rudimentary housing, unimproved toilet facilities and unsafe water, factors that increase the likelihood of chronic disease and exacerbate malnutrition and poor labour productivity. Conclusion This study provides key information about the health and livelihood status of cocoa growers in Bougainville. If productivity is to increase, farmer health needs to improve including improving water and sanitation practices and diets. Building a responsive health system for the community is a challenge when a majority of the population live in small villages with difficult access to health centres. Establishing and integrating outreach village health clinics will enable health care to be more accessible to these remote communities., Highlights • Cocoa productivity in Bougainville remains low. • There are major constraints improved livelihoods for cocoa farmers. • Many households are food insecure with unimproved water and sanitation. • An accumulation of conditions may limit capacity to sell cocoa. • A One Health approach can identify and address many factors impacting cocoa farmers livelihoods.

Arbaeen is an annual religious procession in Iraq with an estimated 17-20 million participants. Public health risks associated with such a mass gathering can be serious at both local and global levels. This is the first quantitative examination of risk factors for, and symptoms of, infectious disease among Arbaeen participants.A cross-sectional survey was conducted of a convenience sample of 191 Arbaeen participants in 2017. Interviewers administered a structured questionnaire. Questions included food sources, preventive measures used and symptoms of infectious diseases during the procession.Data were collected for 191 participants (143 males, 58 females). The most prevalent symptoms were respiratory (runny nose: 22.6%, cough: 22.5%). Diarrhoea was reported by 12.6% of participants, with a strong association with high-income country origin and eating (commercial) street food (odds ratios 6.1 and 4.1, respectively, p 0.05). All symptoms investigated, except breathlessness, were more prevalent in high-income country participants (p 0.05).Street food and high-income country origin were independent risk factors for respiratory or gastrointestinal infection symptoms in this sample of Arbaeen participants. However, these results cannot be generalised due to possible selection bias. Further studies are required to inform policy development and health system preparedness to reduce Arbaeen-associated health risks.

Salmonella enterica serovar Wangata (S. Wangata) is an important cause of endemic salmonellosis in Australia, with human infections occurring from undefined sources. This investigation sought to examine possible environmental and zoonotic sources for human infections with S. Wangata in north-eastern New South Wales (NSW), Australia. The investigation adopted a One Health approach and was comprised of three complimentary components: a case–control study examining human risk factors; environmental and animal sampling; and genomic analysis of human, animal and environmental isolates. Forty-eight human S. Wangata cases were interviewed during a 6-month period from November 2016 to April 2017, together with 55 Salmonella Typhimurium (S. Typhimurium) controls and 130 neighbourhood controls. Indirect contact with bats/flying foxes (S. Typhimurium controls (adjusted odds ratio (aOR) 2.63, 95% confidence interval (CI) 1.06–6.48)) (neighbourhood controls (aOR 8.33, 95% CI 2.58–26.83)), wild frogs (aOR 3.65, 95% CI 1.32–10.07) and wild birds (aOR 6.93, 95% CI 2.29–21.00) were statistically associated with illness in multivariable analyses. S. Wangata was detected in dog faeces, wildlife scats and a compost specimen collected from the outdoor environments of cases’ residences. In addition, S. Wangata was detected in the faeces of wild birds and sea turtles in the investigation area. Genomic analysis revealed that S. Wangata isolates were relatively clonal. Our findings suggest that S. Wangata is present in the environment and may have a reservoir in wildlife populations in north-eastern NSW. Further investigation is required to better understand the occurrence of Salmonella in wildlife groups and to identify possible transmission pathways for human infections.

With rising population numbers, anthropogenic changes to our environment and unprecedented global connectivity, the World Economic Forum ranks the spread of infectious diseases second only to water crises in terms of potential global impact. Addressing the diverse challenges to human health and well-being in the 21st century requires an overarching focus on ‘Planetary Health’, with input from all sectors of government, non-governmental organisations, academic institutions and industry. To clarify and advance the Planetary Health agenda within Australia, specifically in relation to emerging infectious diseases (EID) and antimicrobial resistance (AMR), national experts and key stakeholders were invited to a facilitated workshop. EID themes identified included animal reservoirs, targeted surveillance, mechanisms of emergence and the role of unrecognised human vectors (the ‘invisible man’) in the spread of infection. Themes related to AMR included antimicrobial use in production and companion animals, antimicrobial stewardship, novel treatment approaches and education of professionals, politicians and the general public. Effective infection control strategies are important in both EID and AMR. We provide an overview of key discussion points, as well as important barriers identified and solutions proposed.

In this review, Ebolavirus Disease (EVD) outbreaks have been comprehensively reviewed from their beginning until now. It chronologically discusses how each outbreak was tackled, national and international actions taken, diagnostic methods applied, the infection control procedures put in place, and the lessons learnt from each epidemic for the control of subsequent epidemics. Data for this review were obtained from literature published between 1967 and 2016 in key medical databases, the official websites of various governmental organisations, international public health agencies, and regulatory bodies. Despite major developments in the field of EVD, there has been little progress in its specific therapy or prevention. Historically, individuals who recovered from EVD acted as a source of fresh frozen plasma (containing IgG) that has been used to treat other acutely ill patients, however this therapeutic modality has limitations due to the risk of transmission of blood-borne infections. With the use of advanced and efficient purification methods the incidence of unwanted side effects following immune serum therapy has currently been greatly reduced. Creation of a safe plasma pool that covers immunoglobulins against all strains of EVD is now a research priority. Recommendations on how future EVD outbreaks can be better managed have been discussed.

This deposit is composed by a publication in which the IGC's authors have had the role of collaboration (it's a collaboration publication). This type of deposit in ARCA is in restrictedAccess (it can't be in open access to the public), and can only be accessed by two ways: either by requesting a legal copy from the author (the email contact present in this deposit) or by visiting the following link: https://www.nature.com/articles/s41588-018-0074-3 This publication hasn't any creative commons license associated. This deposit is composed simultaneously by the original published article and also by the "correction" for the published article (erratum). The link for the original article: https://www.nature.com/articles/s41588-017-0029-0#Ack1 This deposit is composed by the main article plus the supplementary materials of the publication. In the version of this article initially published, the URL listed for TubercuList was incorrect. The correct URL is https://mycobrowser.epfl.ch/. The error has been corrected in the HTML and PDF versions of the article. To characterize the genetic determinants of resistance to antituberculosis drugs, we performed a genome-wide association study (GWAS) of 6,465 Mycobacterium tuberculosis clinical isolates from more than 30 countries. A GWAS approach within a mixed-regression framework was followed by a phylogenetics-based test for independent mutations. In addition to mutations in established and recently described resistance-associated genes, novel mutations were discovered for resistance to cycloserine, ethionamide and para-aminosalicylic acid. The capacity to detect mutations associated with resistance to ethionamide, pyrazinamide, capreomycin, cycloserine and para-aminosalicylic acid was enhanced by inclusion of insertions and deletions. Odds ratios for mutations within candidate genes were found to reflect levels of resistance. New epistatic relationships between candidate drug-resistance-associated genes were identified. Findings also suggest the involvement of efflux pumps (drrA and Rv2688c) in the emergence of resistance. This study will inform the design of new diagnostic tests and expedite the investigation of resistance and compensatory epistatic mechanisms. The project was supported by the KAUST faculty baseline research fund (BAS/1/1020-01-01) to A.P. The authors wish to thank members of the KAUST Bioscience Core laboratory who sequenced samples. We thank the Wellcome Trust Sanger Institute core and pathogen sequencing and informatics teams who were involved in the Malawi and Uganda studies. The work was funded in part by the Wellcome Trust (grant numbers WT096249/Z/11/B, WT088559MA, WT081814/Z/06/Z and WT098051) and the Wellcome Trust–Burroughs Wellcome Fund Infectious Diseases Initiative grant (number 063410/ABC/00/Z). F.C. was the recipient of a Bloomsbury College PhD Studentship and was supported by the Wellcome Trust (201344/Z/16/Z); J. Perdigão received a Fundação para a Ciência e a Tecnologia (Portugal) postdoctoral fellowship fund (SFRH/BPD/95406/2013). The Calouste Gulbenkian Foundation, the Institute Gulbenkian in Lisbon and the European Society of Clinical Microbiology and Infectious Diseases supported the research of C.P., J. Perdigão, I.P. and M.V. J. Phelan is funded by a BBSRC PhD studentship. T.G.C. is funded by the Medical Research Council UK (grant numbers MR/K000551/1, MR/M01360X/1, MR/N010469/1 and MC_PC_15103). N.F. is funded by the Medical Research Council UK (grant number MR/K020420/1). T.M. is supported by the Ministry of Health, Labor and Welfare of Japan (H21-Shinkou-Ippan-008 and H24-Shinkou-Ippan-010). info:eu-repo/semantics/publishedVersion

ObjectivesTo explore and compare the knowledge, attitudes and experiences of doctors, dentists and veterinarians (as prescribers) in relation to antibiotic use and antibiotic resistance (AbR), and to consider the implications of these for policy-making that support a One Health approach.DesignA cross-sectional survey conducted online.SettingDoctors, dentists and veterinarians practising in primary, secondary or tertiary care in Australia.Participants547 doctors, 380 dentists and 403 veterinarians completed the survey.Main outcome measuresPrescribers’ knowledge, attitudes and perceptions of AbR, the extent to which a range of factors are perceived as barriers to appropriate prescribing practices, and perceived helpfulness of potential strategies to improve antibiotic prescribing in practice.ResultsThere was substantial agreement across prescriber groups that action on AbR is required by multiple sectors and stakeholders. However, prescribers externalised responsibility to some extent by seeing the roles of others as more important than their own in relation to AbR. There were common and context-specific barriers to optimal prescribing across the prescriber groups. Prescriber groups generally perceived restrictive policies as unhelpful to supporting appropriate prescribing in their practice.ConclusionsThe results have implications for implementing a One Health approach that involves doctors, dentists and veterinarians as key players to tackling the crisis of AbR. The findings are that (1) prescribers understand and are likely receptive to a One Health policy approach to AbR, (2) policy development should be sensitive to barriers that are specific to individual prescriber groups and (3) the development and introduction of interventions that might be perceived as reducing prescriber autonomy will need to be carefully designed and implemented.

BACKGROUND Mongolia has the fifth highest incidence of tuberculosis (TB) in the Western Pacific Region, with high rates of multidrug-resistant TB (MDR-TB). OBJECTIVE To examine the recent spatiotemporal dynamics of MDR-TB in Mongolia. METHODS All MDR-TB cases diagnosed from 2004 to 2012, identified from the National Tuberculosis Control Programme database, were included in the study. Cases diagnosed from 2006 to 2012 were further examined using spatial scan statistics. RESULTS Few MDR-TB cases (n = 29) were diagnosed before the programmatic management of MDR-TB was introduced in 2006. During 2006-2012, 1106 MDR-TB cases were detected, at an annualised rate of 5.9 cases per 100 000 population. Most (>80%) cases were identified in the 15-44 year age group; 45% were among those aged 15-29 years. Case notification rates were highest in the capital city, Ulaanbaatar, with an increasing trend over time in all locations. Three MDR-TB hotspots were identified, all in close proximity to the Trans-Siberian Railway line. The majority of the MDR-TB isolates were resistant to all first-line drugs tested. CONCLUSION Spatiotemporal analysis indicates likely cross-border spread of MDR-TB along the Trans-Siberian Railway line, with subsequent spatial expansion across Mongolia. The frequency of MDR-TB among young patients with pan-resistance to all first-line drugs suggests ongoing MDR-TB transmission within the community.

The control of food-borne outbreaks caused by Listeria monocytogenes in humans relies on the timely identification of food or environmental sources and the differentiation of outbreak-related isolates from unrelated ones. This study illustrates the utility of whole-genome sequencing for examining the link between clinical and environmental isolates of L. monocytogenes associated with an outbreak of hospital-acquired listeriosis in Sydney, Australia. Comparative genomic analysis confirmed an epidemiological link between the three clinical and two environmental isolates. Single nucleotide polymorphism (SNP) analysis showed that only two SNPs separated the three human outbreak isolates, which differed by 19 to 20 SNPs from the environmental isolates and 71 to >10,000 SNPs from sporadic L. monocytogenes isolates. The chromosomes of all human outbreak isolates and the two suspected environmental isolates were syntenic. In contrast to the genomes of background sporadic isolates, all epidemiologically linked isolates contained two novel prophages and a previously unreported clustered regularly interspaced short palindromic repeat (CRISPR)-associated (Cas) locus subtype sequence. The mobile genetic element (MGE) profile of these isolates was distinct from that of the other serotype 1/2b reference strains and sporadic isolates. The identification of SNPs and clonally distinctive MGEs strengthened evidence to distinguish outbreak-related isolates of L. monocytogenes from cocirculating endemic strains.

Background Seven drugs are licensed for the treatment of chronic hepatitis B (CHB) in the United Kingdom. Which initial treatment, secondary therapy, and whether antivirals should be given alone or in combination are questions of considerable uncertainty. Objective The aim of this model was to undertake a comprehensive economic evaluation of all antiviral treatments for CHB to recommend the most cost-effective therapeutic sequence. Methods We developed a probabilistic Markov model to compare the cost-effectiveness of all clinically relevant antiviral treatment sequences for nucleos(t)ide-naive adults with hepatitis B e-antigen (HBeAg)-positive or HBeAg-negative CHB. Relative rates of HBeAg seroconversion and viral suppression were obtained from a network meta-analysis. Data on mortality, antiviral drug resistance, durability of response, adverse events, and costs were obtained from published literature. Results are reported in terms of lifetime costs, quality-adjusted life-years (QALYs), and expected net benefit. Results In the base-case analysis, pegylated interferon alpha-2a (peg-IFN α-2a) followed by tenofovir disoproxil fumarate was most effective and cost-effective in HBeAg-positive patients, with a cost of £7488 per QALY gained compared with no treatment. In HBeAg-negative patients, peg-IFN α-2a followed by entecavir was most effective and cost-effective, with a cost of £6981 per QALY gained. The model was robust to a wide range of sensitivity analyses. Conclusions Peg-IFN α-2a followed by tenofovir disoproxil fumarate or entecavir is the most effective antiviral treatment strategy for people with both variants of CHB. At a cost of less than £10,000 per QALY gained, these sequences are considered cost-effective in England and Wales. The results of this analysis were used to inform 2013 National Institute for Health and Care Excellence guideline recommendations.

Infant botulism is a potentially life-threatening paralytic disease that can be associated with prolonged morbidity if not rapidly diagnosed and treated. Four infants were diagnosed and treated for infant botulism in NSW, Australia, between May 2011 and August 2013. Despite the temporal relationship between the cases, there was no close geographical clustering or other epidemiological links. Clostridium botulinum isolates, three of which produced botulism neurotoxin serotype A (BoNT/A) and one BoNT serotype B (BoNT/B), were characterized using whole-genome sequencing (WGS). In silico multilocus sequence typing (MLST) found that two of the BoNT/A-producing isolates shared an identical novel sequence type, ST84. The other two isolates were single-locus variants of this sequence type (ST85 and ST86). All BoNT/A-producing isolates contained the same chromosomally integrated BoNT/A2 neurotoxin gene cluster. The BoNT/B-producing isolate carried a single plasmid-borne bont /B gene cluster, encoding BoNT subtype B6. Single nucleotide polymorphism (SNP)-based typing results corresponded well with MLST; however, the extra resolution provided by the whole-genome SNP comparisons showed that the isolates differed from each other by >3,500 SNPs. WGS analyses indicated that the four infant botulism cases were caused by genomically distinct strains of C. botulinum that were unlikely to have originated from a common environmental source. The isolates did, however, cluster together, compared with international isolates, suggesting that C. botulinum from environmental reservoirs throughout NSW have descended from a common ancestor. Analyses showed that the high resolution of WGS provided important phylogenetic information that would not be captured by standard seven-loci MLST.

International audience; To characterize the genetic determinants of resistance to antituberculosis drugs, we performed a genome-wide association study (GWAS) of 6,465 $Mycobacterium\ tuberculosis$ clinical isolates from more than 30 countries. A GWAS approach within a mixed-regression framework was followed by a phylogenetics-based test for independent mutations. In addition to mutations in established and recently described resistance-associated genes, novel mutations were discovered for resistance to cycloserine, ethionamide and para-aminosalicylic acid. The capacity to detect mutations associated with resistance to ethionamide, pyrazinamide, capreomycin, cycloserine and para-aminosalicylic acid was enhanced by inclusion of insertions and deletions. Odds ratios for mutations within candidate genes were found to reflect levels of resistance. New epistatic relationships between candidate drug-resistance-associated genes were identified. Findings also suggest the involvement of efflux pumps ($drrA$ and $Rv2688c$) in the emergence of resistance. This study will inform the design of new diagnostic tests and expedite the investigation of resistance and compensatory epistatic mechanisms.

An outbreak of multi-drug resistant (MDR) tuberculosis (TB) has been reported on Daru Island, Papua New Guinea. Mycobacterium tuberculosis strains driving this outbreak and the temporal accrual of drug resistance mutations have not been described. Whole genome sequencing of 100 of 165 clinical isolates referred from Daru General Hospital to the Supranational reference laboratory, Brisbane, during 2012-2015 revealed that 95 belonged to a single modern Beijing sub-lineage strain. Molecular dating suggested acquisition of streptomycin and isoniazid resistance in the 1960s, with potentially enhanced virulence mediated by an mycP1 mutation. The Beijing sub-lineage strain demonstrated a high degree of co-resistance between isoniazid and ethionamide (80/95; 84.2 %) attributed to an inhA promoter mutation combined with inhA and ndh coding mutations. Multi-drug resistance, observed in 78/95 samples, emerged with the acquisition of a typical rpoB mutation together with a compensatory rpoC mutation in the 1980s. There was independent acquisition of fluoroquinolone and aminoglycoside resistance, and evidence of local transmission of extensively drug resistant (XDR) strains from 2009. These findings underline the importance of whole genome sequencing in informing an effective public health response to MDR/XDR TB.

Background Mycobacterium tuberculosis (MTB) PE_PGRS genes belong to the PE multigene family. Although the function of PE_PGRS genes is unknown, it is hypothesized that the PE_PGRS genes may be associated with antigenic variability in MTB. Material and methods Whole genome sequencing analysis was performed on (n = 37) extensively drug-resistant (XDR) MTB strains from Pakistan, which included Lineage 1 (East African Indian, n = 2); Other lineage 1 (n = 3); Lineage 3 (Central Asian, n = 24); Other lineage 3 (n = 4); Lineage 4 (X3, n = 1) and T group (n = 3) MTB strains. Results There were 107 SNPs identified from the analysis of 42 PE_PGRS genes; of these, 13 were non-synonymous SNPs (nsSNPs). The nsSNPs identified in PE_PGRS genes – 6, 9 and 10 – were common in all EAI, CAS, Other lineages (1 and 3), T1 and X3. Deletions (DELs) in PE_PGRS genes – 3 and 19 – were observed in 17 (80.9%) CAS1 and 6 (85.7%) in Other lineages (1 and 3) XDR MTB strains, while DELs in the PE_PGRS49 were observed in all CAS1, CAS, CAS2 and Other lineages (1 and 3) XDR MTB strains. All CAS, EAI and Other lineages (1 and 3) strains showed insertions (INS) in PE_PGRS6 gene, while INS in the PE_PGRS genes 19 and 33 were observed in 20 (95.2%) CAS1, all CAS, CAS2, EAI and Other lineages (1 and 3) XDR MTB strains. Conclusion Genetic diversity in PE_PGRS genes contributes to antigenic variability and may result in increased immunogenicity of strains. This is the first study identifying variations in nsSNPs and INDELs in the PE_PGRS genes of XDR-TB strains from Pakistan. It highlights common genetic variations which may contribute to persistence.

OBJECTIVES: Alemtuzumab is a newly licensed treatment of active relapsing-remitting multiple sclerosis (RRMS) in Europe, which in phase II and III studies demonstrated superior efficacy over β-interferon in reducing disability progression over 2-3 years. In this observational cohort study, we sought to describe our longer-term experience of the efficacy and safety of alemtuzumab in active RRMS. METHODS: Clinical and laboratory data including serial Expanded Disability Status Scale (EDSS) assessments, from all 87 patients treated with alemtuzumab on investigator-led studies in Cambridge, UK, from 1999 to 2012, were collected. The occurrence of adverse events including secondary autoimmunity, malignancy and death, and pregnancy outcomes was recorded. Baseline variables including age, disease duration and relapse rate were compared in univariate and logistic regression analyses between groups with different disability outcomes. RESULTS: Over a median 7-year follow-up (range 33-144 months), most patients (52%) required just two cycles of alemtuzumab. In the remaining patients, relapses triggered re-treatment to a total of three cycles (36%), four cycles (8%) or five cycles (1%). Using a 6-month sustained accumulation of disability definition, 59/87 (67.8%) of patients had an improved or unchanged disability compared with baseline. By an area under the curve analysis, 52/87 (59.8%) patients had an overall improvement or stabilisation of disability. Higher baseline relapse rate was associated with worse long-term disability outcomes, with trends for longer disease duration and older age at first treatment. Secondary autoimmunity was the most frequent adverse event occurring in 41/86 (47.7%) patients, most commonly involving the thyroid gland. CONCLUSIONS: Alemtuzumab is associated with disease stabilisation in the majority of patients with highly active RRMS over an average seven-year follow-up. No new safety concerns arose over this extended follow-up.

Infectious diseases remain responsible for significant global morbidity and mortality, and diseases emerge and re-emerge in sometimes unpredictable locations and at unpredictable times. Although much is known about how to detect and respond to existing infections, more public health research is needed to predict the likelihood of their emergence and spread, and to improve the precision and timeliness of public health responsiveness. To achieve this, further research is required to develop pathogen genomics from more than just a tool for outbreak investigation to one that will identify and quantify catalysts for emergence within a given population. More research is also needed to develop digital epidemiology techniques to identify syndromic clusters earlier. Beyond human public health, appreciating how animals and the environment affect disease emergence presents us with a new challenge: to develop truly interdisciplinary research that encompasses all aspects of pathogen surveillance and response. This includes understanding why microorganisms cross species to cause diseases (e.g. from animals to humans), factors that drive spread of infections, and systems research that will result in development of joint responses to outbreaks from different professional, government and international groups. Only then will we be better prepared for the next outbreak.

Background There is a large increase in the numbers of refugees and asylum seekers worldwide and a lack of data on the carriage of antimicrobial resistance in refugee/asylum seeking groups. Methods This article aims to identify the impact of refugees and asylum seekers on the acquisition and transmission of antimicrobial resistance (AMR) through a literature search. The databases Embase, Medline, Pubmed, and Web of Science Core Collection were utilised and covered all articles before the 1st of October 2016. In total, 577 articles were identified, and studies were eligible if they met the selection criteria, including observational study design, English language, and AMR strains reported in absolute numbers. In total, 17 articles met the criteria, the majority were from the European region. Results Articles fitting the selection criteria exclusively reported AMR in bacterial species including Mycobacterium tuberculosis, Escherichia coli, Klebsiella pneumonia, K. oxytoca, Shigella spp., Staphylococcus aureus , Enterococcus faecium, and Acinetobacter baumannii. The analyses indicated that a high percentage of AMR strains, have been circulating among refugees and asylum seekers. Conclusion The displacement of refugees and asylum seekers seem to play a key role in the transmission of AMR. Therefore, improved AMR control measures are essential. A knowledge gap was identified; further research is strongly recommended.

Biological therapies, even humanized mAbs, may induce antiglobulin responses that impair efficacy. We tested a novel strategy to induce tolerance to a therapeutic mAb. Twenty patients with relapsing–remitting multiple sclerosis received an initial cycle of alemtuzumab (Campath-1H), up to 120 mg over 5 d, preceded by 500 mg SM3. This Ab differs from alemtuzumab by a single point mutation and is designed not to bind to cells. Twelve months later, they received a second cycle of alemtuzumab, up to 72 mg over 3 d. One month after that, 4 of 19 (21%) patients had detectable serum anti-alemtuzumab Abs compared with 145 of 197 (74%) patients who received two cycles of alemtuzumab without SM3 in the phase 2 CAMMS223 trial (p < 0.001). The efficacy and safety profile of alemtuzumab was unaffected by SM3 pretreatment. Long-lasting “high-zone” tolerance to a biological therapy may be induced by pretreatment with a high i.v. dose of a drug variant, altered to reduce target-binding.

Background Combating the spread of drug resistant tuberculosis is a global health priority. Whole genome association studies are being applied to identify genetic determinants of resistance to anti-tuberculosis drugs. Protein structure and interaction modelling are used to understand the functional effects of putative mutations and provide insight into the molecular mechanisms leading to resistance. Methods To investigate the potential utility of these approaches, we analysed the genomes of 144 Mycobacterium tuberculosis clinical isolates from The Special Programme for Research and Training in Tropical Diseases (TDR) collection sourced from 20 countries in four continents. A genome-wide approach was applied to 127 isolates to identify polymorphisms associated with minimum inhibitory concentrations for first-line anti-tuberculosis drugs. In addition, the effect of identified candidate mutations on protein stability and interactions was assessed quantitatively with well-established computational methods. Results The analysis revealed that mutations in the genes rpoB (rifampicin), katG (isoniazid), inhA-promoter (isoniazid), rpsL (streptomycin) and embB (ethambutol) were responsible for the majority of resistance observed. A subset of the mutations identified in rpoB and katG were predicted to affect protein stability. Further, a strong direct correlation was observed between the minimum inhibitory concentration values and the distance of the mutated residues in the three-dimensional structures of rpoB and katG to their respective drugs binding sites. Conclusions Using the TDR resource, we demonstrate the usefulness of whole genome association and convergent evolution approaches to detect known and potentially novel mutations associated with drug resistance. Further, protein structural modelling could provide a means of predicting the impact of polymorphisms on drug efficacy in the absence of phenotypic data. These approaches could ultimately lead to novel resistance mutations to improve the design of tuberculosis control measures, such as diagnostics, and inform patient management. Electronic supplementary material The online version of this article (doi:10.1186/s12916-016-0575-9) contains supplementary material, which is available to authorized users.

Background Alemtuzumab is a lymphocyte depleting monoclonal antibody that has demonstrated superior efficacy over interferon β-1a for relapsing–remitting multiple sclerosis (MS), and is currently under investigation in phase 3 trials. One unresolved issue is the duration and significance of the lymphopenia induced. The long term effects on lymphocyte reconstitution of a single course, and the consequences that this has on disability, morbidity, mortality and autoimmunity, were examined. Methods The lymphocyte reconstitution (n=36; 384 person years) and crude safety data (n=37; 447 person years) are reported for the first patients with progressive MS to receive alemtuzumab (1991–1997). Reconstitution time was expressed as a geometric mean or, when a non-negligible number of individuals failed to recover, as a median using survival analysis. Results Geometric mean recovery time (GMRT) of total lymphocyte counts to the lower limit of the normal range (LLN; ≥1.0×10 9 cells/l) was 12.7 months (95% CI 8.8 to 18.2 months). For B cells, GMRT to LLN (≥0.1×10 9 /l) was 7.1 months (95% CI 5.3 to 9.5); median recovery times for CD8 (LLN ≥0.2×10 9 cells/l) and CD4 lymphocytes (LLN ≥0.4×10 9 cells/l) were 20 months and 35 months, respectively. However, CD8 and CD4 counts recovered to baseline levels in only 30% and 21% of patients, respectively. No infective safety concerns arose during 447 person years of follow-up. Conclusions Lymphocyte counts recovered to LLN after a single course of alemtuzumab in approximately 8 months (B cells) and 3 years (T cell subsets), but usually did not recover to baseline values. However, this long lasting lymphopenia in patients with a previously normal immune system was not associated with an increased risk of serious opportunistic infection.

Urinary tract infections (UTIs) associated with Escherichia coli are a growing threat with an increase in the prevalence of multidrug resistant (MDR) strains, particularly ß-lactamase producers, occurring globally. We investigated the presence of carbapenem-resistant uropathogenic E. coli clones in community-acquired UTIs in Riyadh, Kingdom of Saudi Arabia (KSA) to identify the virulence and resistance structures of the resistant clones and relate the isolates to those circulating globally. A combination of comparative genomics and phenotypic approaches were used to characterize ten MDR-uropathogenic Escherichia coli isolates recovered from UTI patients in Riyadh between November 2014 and January 2015. We report the presence of NDM-1 and 5, and OXA-181 in carbapenem-resistant UPEC strains from Riyadh, KSA. Single nucleotide polymorphism analyses demonstrated that these ten isolates fell into four phylogenetically distinct clades within the UPEC phylogeny. Comparative genomic analyses indicate that these diverse clones could be distinguished according to their multilocus sequencing type (MLST), serology, and virulence and antimicrobial gene architectures. These clones include the blaNDM-1 carrying isolates of the globally predominant MDR ST131 and ST69 types, previously identified as one of the most common UPEC strains in KSA. This is in addition to clones of ST23Cplx (ST410) and ST448Cplx (ST448) that have likely evolved from common intestinal strains, carrying copies of ß-lactamase genes including blaNDM-5, blaCTX-M-15, blaTEM-1, blaCMY-42, blaOXA-1 and blaOXA-181. These data have identified an emerging public health concern and highlight the need to use comprehensive approaches to detect the structure of MDR E. coli populations associated with community-acquired UTIs in KSA.

Human infections with Salmonella enterica subspecies enterica serovar Senftenberg are often associated with exposure to poultry flocks, farm environments, or contaminated food. The recent emergence of multidrug-resistant isolates has raised public health concerns. In this study, comparative genomics and phenotypic analysis were used to characterize 14 Salmonella Senftenberg clinical isolates recovered from multiple outbreaks in Shenzhen and Shanghai, China, between 2002 and 2011. Single-nucleotide polymorphism analyses identified two phylogenetically distinct clades of S . Senftenberg, designated SC1 and SC2, harboring variations in Salmonella pathogenicity island 1 (SPI-1) and SPI-2 and exhibiting distinct biochemical and phenotypic signatures. Although the two variants shared the same serotype, the SC2 isolates of sequence type 14 (ST14) harbored intact SPI-1 and -2 and hence were characterized by possessing efficient invasion capabilities. In contrast, the SC1 isolates had structural deletion patterns in both SPI-1 and -2 that correlated with an impaired capacity to invade cultured human cells and also the year of their isolation. These atypical SC1 isolates also lacked the capacity to produce hydrogen sulfide. These findings highlight the emergence of atypical Salmonella Senftenberg variants in China and provide genetic validation that variants lacking SPI-1 and regions of SPI-2, which leads to impaired invasion capacity, can still cause clinical disease. These data have identified an emerging public health concern and highlight the need to strengthen surveillance to detect the prevalence and transmission of nontyphoidal Salmonella species.

Australia has a low tuberculosis incidence rate with most cases occurring among recent immigrants. Given suboptimal cluster resolution achieved with 24-locus mycobacterium interspersed repetitive unit (MIRU-24) genotyping, the added value of whole genome sequencing was explored. MIRU-24 profiles of all Mycobacterium tuberculosis culture-confirmed tuberculosis cases diagnosed between 2009 and 2013 in New South Wales (NSW), Australia, were examined and clusters identified. The relatedness of cases within the largest MIRU-24 clusters was assessed using whole genome sequencing and phylogenetic analyses. Of 1841 culture-confirmed TB cases, 91.9% (1692/1841) had complete demographic and genotyping data. East-African Indian (474; 28.0%) and Beijing (470; 27.8%) lineage strains predominated. The overall rate of MIRU-24 clustering was 20.1% (340/1692) and was highest among Beijing lineage strains (35.7%; 168/470). One Beijing and three East-African Indian (EAI) clonal complexes were responsible for the majority of observed clusters. Whole genome sequencing of the 4 largest clusters (30 isolates) demonstrated diverse single nucleotide polymorphisms (SNPs) within identified clusters. All sequenced EAI strains and 70% of Beijing lineage strains clustered by MIRU-24 typing demonstrated distinct SNP profiles. The superior resolution provided by whole genome sequencing demonstrated limited M. tuberculosis transmission within NSW, even within identified MIRU-24 clusters. Routine whole genome sequencing could provide valuable public health guidance in low burden settings.

Although Bacillus Calmette-Guérin (BCG) vaccines against tuberculosis have been available for more than 90 years, their effectiveness has been hindered by variable protective efficacy and a lack of lasting memory responses. One factor contributing to this variability may be the diversity of the BCG strains that are used around the world, in part from genomic changes accumulated during vaccine production and their resulting differences in gene expression. We have compared the genomes and transcriptomes of a global collection of fourteen of the most widely used BCG strains at single base-pair resolution. We have also used quantitative proteomics to identify key differences in expression of proteins across five representative BCG strains of the four tandem duplication (DU) groups. We provide a comprehensive map of single nucleotide polymorphisms (SNPs), copy number variation and insertions and deletions (indels) across fourteen BCG strains. Genome-wide SNP characterization allowed the construction of a new and robust phylogenic genealogy of BCG strains. Transcriptional and proteomic profiling revealed a metabolic remodeling in BCG strains that may be reflected by altered immunogenicity and possibly vaccine efficacy. Together, these integrated-omic data represent the most comprehensive catalogue of genetic variation across a global collection of BCG strains.

Respiratory syncytial virus (RSV) is a major cause of viral acute respiratory tract infections in young children. The virus is characterised by distinct seasonality that is dependent upon the latitude and its ability to cause reinfection. Respiratory syncytial virus demonstrates a complex molecular epidemiology pattern as multiple strains and/or genotypes cocirculate during a single epidemic. Previous studies have investigated the relationship between RSV genetic diversity, reinfection, and clinical features. Here, we review the evidence behind this relationship together with the impact that the advancement of whole genome sequencing will have upon our understanding and the need for reconsidering the classification of RSV genotypes.